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Acromegaly Cases Exhibiting Increased Growth Hormone Levels during Oral Glucose Loading with Preadministration of Dipeptidyl Peptidase-4 Inhibitor.

ABSTRACT: Objective Glucose-dependent insulinotropic polypeptide (GIP) is speculated to worsen growth hormone (GH) hypersecretion in acromegaly and to be a cause of paradoxical increases in GH (PI-GH) during 75-g oral glucose tolerance testing (75-g OGTT). Dipeptidyl peptidase-4 inhibitors (DPP4is), which increase the circulating concentration of active GIP, are frequently administered to diabetic patients, including those with acromegaly. We aimed to determine whether or not the administration of a DPP4i increases GH concentration, especially in patients demonstrating PI-GH during a DPP4i-OGTT, in which a DPP4i was administered immediately before 75-g OGTT. Methods This prospective cross-sectional study was carried out on acromegalic patients admitted to Hokkaido University hospital between June 2011 and May 2018. The participants underwent both 75-g OGTT and DPP4i-OGTT. For those who underwent surgery, immunohistochemical staining and quantitative polymerase chain reaction (PCR) for the GIP receptor (GIPR) were performed on the resected pituitary adenomas. Results Twenty-five percent of the participants had PI-GH confirmed (3 of 12 cases). Two of the three participants who demonstrated PI-GH exhibited higher circulating GH concentrations during DPP4i-OGTT than during OGTT. The increase in plasma glucose was reduced during DPP4i-OGTT compared to during 75-g OGTT, suggesting that the increase in GH during DPP4i-OGTT was due not to high glucose concentrations but instead increased GIP caused by the administration of DPP4i. The adenoma from one participant with PI-GH displayed positive immunostaining for GIPR and a higher GIPR messenger ribonucleic acid (mRNA) expression than the others. Conclusion DPP4i may enhance the GH secretion response during glucose loading, especially in individuals with PI-GH.

SUBMITTER: Oba-Yamamoto C

PROVIDER: S-EPMC8381171 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:Diminished growth hormone (GH) is associated with impaired endothelial function and fibrinolysis. GH-releasing hormone is the primary stimulus for GH secretion and a substrate of dipeptidyl peptidase-4. We tested the hypothesis that dipeptidyl peptidase-4 inhibition with sitagliptin increases stimulated GH secretion, vasodilation, and tissue plasminogen activator (tPA) activity. METHODS AND RESULTS:Healthy adults participated in a 2-part double-blind, randomized, placebo-controlled, crossover study. First, 39 patients (29 women) received sitagliptin or placebo on each of 2 days separated by a washout. One hour after study drug, blood was sampled and then arginine (30 g IV) was given to stimulate GH. Vasodilation was assessed by plethysmography and blood sampled for 150 minutes. Following a washout, 19 of the original 29 women received sitagliptin alone versus sitagliptin plus antagonist to delineate GH receptor (GHR)- (n=5), nitric oxide- (n=7), or glucagon-like peptide-1 receptor- (n=7) dependent effects. Sitagliptin enhanced stimulated GH secretion (P<0.01 versus placebo, for 30 minutes) and free insulin-like growth factor-1 (P<0.001 versus placebo, after adjustment for baseline) in women. Vasodilation and tPA increased in all patients, but sitagliptin enhanced vasodilation (P=0.01 versus placebo) and increased tPA (P<0.001) in women only. GHR blockade decreased free insulin-like growth factor-1 (P=0.04 versus sitagliptin alone) and increased stimulated GH (P<0.01), but decreased vascular resistance (P=0.01) such that nadir vascular resistance correlated inversely with GH (rs=-0.90, P<0.001). GHR blockade suppressed tPA. Neither nitric oxide nor glucagon-like peptide-1 receptor blockade affected vasodilation or tPA. CONCLUSIONS:Sitagliptin enhances stimulated GH, vasodilation, and fibrinolysis in women. During sitagliptin, increases in free insulin-like growth factor-1 and tPA occur via the GHR, whereas vasodilation correlates with GH but occurs through a GHR-independent mechanism. CLINICAL TRIAL REGISTRATION:URL: http://www.clinicaltrials.gov. Unique identifier: NCT01701973.

Project description:BackgroundThe dipeptidyl peptidase-4 (DPP-4) inhibitors Sitagliptin and Vildagliptin lower blood glucose by augmenting endogenous levels of glucagon-like peptide-1 (GLP-1), an incretin which also confers cardioprotection. As such, we hypothesized that treatment with DPP-4 inhibitors are also cardioprotective.MethodsIn ex vivo experiments: Male Sprague-Dawley rats were randomized to receive by oral gavage either Vildagliptin (20 mg/kg/day), Sitagliptin (100 mg/kg/day), or water for 2 weeks. Excised hearts were Langendorff-perfused with buffer containing either 5 mmol/L or 11 mmol/L glucose and subjected to 35 minutes ischaemia/120 minutes reperfusion. In in vivo experiments: Male young Wistar and Sprague-Dawley rats, middle aged Wistar and Goto-Kakizaki diabetic rats were randomized to receive by oral gavage either Sitagliptin (100 mg/kg/day), or water for 2 weeks. Rats were then subjected to 30 minutes ischaemia/120 minutes reperfusion and infarct size ascertained.ResultsTwo weeks pre-treatment with either Vildagliptin or Sitagliptin reduced ex vivo myocardial infarction (MI) size in hearts perfused with buffer containing 11 mmol/L glucose but not 5 mmol/L glucose. This effect was abolished by Exendin 9-39 (GLP-1 receptor antagonist) and H-89 (PKA antagonist). Treatment of perfused hearts with native GLP-1 was also glucose-sensitive, reducing MI size, at glucose concentrations 7, 9, and 11 mmol/L but not at 5 mmol/L. Finally, Sitagliptin reduced in vivo MI size in middle aged Wistar (7-8 mmol/L glucose) and Goto-Kakizaki (9-10 mmol/L glucose) rats where blood glucose was elevated, but not in young Wistar (5 mmol/L glucose) or Sprague-Dawley (5 mmol/L glucose) rats, where blood glucose was normal.ConclusionsWe find that chronic treatment with DPP-4 inhibitors reduced MI size, via the GLP-1 receptor-PKA pathway, in a glucose-dependent manner. Glucose-sensitive cardioprotection of endogenous GLP-1 in diabetic patients may in part explain why intensive control of serum glucose levels has been associated with increased cardiovascular risk.

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Acromegaly Cases Exhibiting Increased Growth Hormone Levels during Oral Glucose Loading with Preadministration of Dipeptidyl Peptidase-4 Inhibitor.

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